Pleural Mesothelioma – Chemotherapy questions

Portal Forums Lung/Thoracic Cancer Mesothelioma Pleural Mesothelioma – Chemotherapy questions

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October 25, 2014 at 1:46 pm  #1266676    

shhs

My brother has pleural mesothelioma – We live in Wellington New Zealand he explains

I haves had: thoraoscopy, biopsy, talc pleuradesys, decortication and re-inflation of my
right lung (W/C 13 10 14). .
I am currently on a ‘trimodal’ treatment plan.

I would however like to ensure that we are doing everything to scour the world for any emerging treatments.

I have epithelial malignant pleural mesothelioma, am fit with no
other health issues and by all accounts have a ‘low disease burden’.

Does chemotherapy lose effectiveness over a number of treatments and why?

My therapy, starting 07 11 14, will be using Alimpta and Platinum for 3
rounds . I understand that this is pretty much the recognised treatment. I seems that a round was 4 weeks in Australia and 3 weeks here in NZ . What is common practice?

Is it common practice to included blood vessel blockers?

I have also seen reference to FGF and FAK inhibitors,
Can you explain what these are?

Hot’ chemo drugs can be applied into chest cavity post surgery. I understand the disease tends to stay local and that direct application of the treatment to the site has the benefit of
applying concentrations that could not otherwise be achieved. Is this view shared by others?

Do mistletoe injections have any good or harmful effects (the are used in Europe)

Thanks

Mike Sparrow

October 25, 2014 at 4:58 pm  #1266678    
Dr West
Dr West

Mike,

I’m very sorry about your brother’s diagnosis. We’re happy to try to help but in the interest of time, it’s only feasible to cover the more central questions, not the ones that are not relevant to treatment.

The standard chemotherapy treatment is definitely cisplatin and Alimta (pemetrexed), most commonly given every 3 weeks. This chemotherapy is not commonly combined with other targeted therapies. There has been a large study that tested the role of Avastin, an angiogenesis inhibitor (“blood vessel blocker”), in mesothelioma and showed that it does not improve outcomes. It is not used in combination with chemotherapy. Nor are targeted therapies like FGF or FAK inhibitors, which are novel therapies that really haven’t demonstrated any clear benefit in cancer at this time. While it would be reasonable to consider them in a clinical trial, they have no role in standard treatment.

The idea of hyperthermic chemotherapy is done in a few centers in the US — I presume also some others in the world. The few places that do it think it helps, but this treatment is very toxic and is very far from being a standard of care.

Mesothelioma is a setting in which there is relatively little research because it’s a very uncommon cancer, and much of what drives treatment is the sometimes very strong opinions of the doctors treating it and the misguided presumption by some doctors and many patients that it must be better to give the most phenomenally aggressive treatment a patient can survive. I would be very cautious about following the zealous opinions of people who are making judgments based on presumptions and faith rather than evidence. What often happens is that the healthiest patients with the lowest cancer burden with the most favorable cancer biology are selected for the most extreme treatments. If they do well, it is attributed to the treatment, even though they were exactly the patients expected to do best anyway.

(cont)

October 25, 2014 at 5:02 pm  #1266679    
Dr West
Dr West

With regard to mistletoe, the short answer is that there is no evidence of any quality to suggest that it should be included in the treatment plan. That treatments are done somewhere is very different from them being useful. People do all sorts of things. I would say that neither I nor any other recognized thoracic oncology expert has ever recommended mistletoe injections for their patients. It wouldn’t crack my top 500 recommendations for patients.

-Dr. West

October 26, 2014 at 5:22 am  #1266681    
Dr West
Dr West

I think that’s a fair assessment of mistletoe for cancer. There isn’t enough research to say much either way. There’s always a potential danger, just as there is always a potential benefit, when interventions haven’t been assessed enough to say more, but otherwise I’d say the leading risk is simply false hope that it’s going to have a major effect. Perhaps, but I wouldn’t presume that.

Good luck.

-Dr. West

October 26, 2014 at 2:57 pm  #1266690    

shhs

Thanks reply

No risk of false hope vis a vie mistletoe

The real difficulty is obtaining data

– 5 and 10 year survival rates for the
– ‘trimodal approach,
-verses the chemo and radiation
– verses chemo only

When betting ones life and you are ‘doomed if you do- doomed if you don’t – without the data
its hard to make an informed decision.

Mike

October 27, 2014 at 7:34 am  #1266697    
Dr West
Dr West

Studies are too small to rely on data here. These aren’t randomized trials: they are small numbers of patients, usually carefully selected, getting treated at only a few centers. I don’t think it’s really possible to generalize a broader experience without a randomized trial in which half of the patients get trimodality therapy and half of the patients receive a different, less aggressive approach. Another approach that is gaining traction among some experts is the so-called “Toronto approach” (developed in Toronto, also called SMART therapy, an acronym I can’t remember the origin of the acronym for) in which patients receive 5 days of high dose radiation to the entire half-chest with the mesothelioma. followed immediately by an extrapleural pneumonectomy, followed by follow-up and no planned chemotherapy unless or until the cancer recurs.

I’ll say that one approach that I still think is very reasonable in an an asymptomatic (no symptoms) patient with a small volume of mesothelioma is to follow it without treatment, until clear progression, if a patient can psychologically deal with that. Mesothelioma can sometimes develop over yers, sometimes over MANY years, and I’m very unconvinced that the long-term survivors of super-aggressive approaches to mesothelioma aren’t just the same people who would have been alive ANYWAY 3-5 or even 10 years later if their mesothelioma had been left untreated or treated just with chemotherapy. To some surgeons, suggesting as much is sacrilege, but all of the approaches for potentially resectable mesothelioma are more based in faith and bias than actual evidence. I can assure you that I follow some patients with an indolent mesothelioma that shows barely perceptible change every 4-6 months on scans, whether I give chemo or not, and others respond well enough to chemo that I can treat them for years and years with minimal side effects.

It may not help to know of so many options, but there’s much room for patient preference.

-Dr. West

October 27, 2014 at 11:00 am  #1266702    

shhs

As always thank you for your time.

In Simon’s case he started getting plural effusions that had to be drained – suggesting perhaps the mesothelioma was becoming less ‘indolent’. The diagnosis followed the effusions.

The book “Cancer – the emperor of all maladies” talked of how in the ‘war on cancer ‘ the radical surgery and later radical chemotherapy approaches were ideologically driven – with the best intentions. This also being your message.

The difficulty with patient preference – is that also faith based on a lot less knowledge

Questions

1. I thought the cancer cells became desensitised to the chemotherapy hence limiting the number of time it could be used – is this not the case?

2. Are changes monitored at the cellular level (e.g taking more biopsies) or only using scans? Using scans is it easy to miss significant changes and the you miss the window for treatment options?

3. Do you know which centres are practicing the ‘Toronto approach’

Regards

Mike Sparrow

October 27, 2014 at 2:32 pm  #1266703    
catdander forum moderator
catdander forum moderator

Hi Mike, I’ve been out of www range for a few days and haven’t had a chance to welcome you to Grace. I’m so sorry your brother is going through this. It sounds like Simon is lucky to have you in his corner.

It’s true cancer mutates to grow through chemo drugs also each individual’s system can only withstand so much of a drug. For both these reasons people with stage IV lung cancer are usually better off using only enough treatment to feel well as long as possible. A metaphor about living with non curable lung cancer is that of a foot race where treatment is a marathon as opposed to a sprint.

There are growing reasons today to look at current biopsies when so called targeted treatments are used such as those with an EGFR mutation have been using 1st gen drug like erlotinib then begin to progress (cancer mutates to grow through treatment). Doctors have found specific mutations that happen and have found drugs that work around the new mutation. But this is a specific only to those cases in which people have an EGFR, ALK, ROS1 mutation. For the rest/most people scanning is still the best way to watch what’s happening. There’s not information found in a biopsy that can alter treatment decisions. If there is reason to doubt a spot found on scan may or may not be cancer a biopsy may be in order.

I hope this is helpful. Best of luck to you and your brother. I hope he does well for a long long time to come.

Janine

October 27, 2014 at 2:47 pm  #1266705    
catdander forum moderator
catdander forum moderator

While looking for info on “Toronto approach” I came across this,though not any new info, http://www.mesothelioma.com/blog/authors/jack/trimodality-therapy-for-mesothelioma-better-results-because-or-despite-aggressive-treatment.htm

October 27, 2014 at 4:30 pm  #1266709    
JimC Forum Moderator
JimC Forum Moderator

Hi Mike,

I just to add some thoughts to the good information Janine provided. Although it is true that for the most part a particular chemo drug eventually becomes ineffective, there are patients who remain on a single drug (especially in the case of targeted therapies) for an extended period. Patients are monitored with scans and if progression is seen, the recent trend (as Janine pointed out) is to re-biopsy to see if there is a new mutation for which a targeting drug has been developed.

If there is no progression, usually doctors will not re-biopsy, preferring to re-scan and perform clinical examinations of the patient. One reason is that biopsies are invasive procedures which are not risk-free, so they are only done when they will directly affect the management of the cancer. If you biopsy when there is no progression, you may discover a new mutation but if it’s not causing trouble it would be premature to initiate treatment. If progression later appears, you would probably still need a new biopsy to be assured that it is the same mutation which is causing the progression so that the proper treatment can be selected.

JimC
Forum moderator


Jul 2008 Wife Liz (51/never smoker) Dx Stage IV NSCLC EGFR exon 19
4 cycles Carbo/alimta, 65% shrinkage
Tarceva maintenance
Mar 2010 progression, added Alimta, stable
Sep 2010 multiple brain mets, WBR
Oct 2010 large pericardial effusion, tamponade
Jan 2011 progression, start abraxane
Jun 2011-New liver, brain mets, add Tarceva
Oct 2011-Dx Leptomeningeal carcinomatosis; pulsed Tarceva
At rest Nov 4 2011
Since then: http://cancergrace.org/blog/jim-and-lisa

October 27, 2014 at 6:06 pm  #1266712    
Dr West
Dr West

Not much to add. Scans (and symptoms) are definitely the way we monitor the pace of the disease, which almost invariably tends to accelerate over time, though sometimes that’s just from “extremely indolent” to “still pretty indolent, but less so” over many years (admittedly, the best case scenario).

I couldn’t say where the Toronto approach is being done. The surgeon discussing surgery options would be in the best position to speak to this, but I don’t want to imply that this is the clear standard of care right now or that I am definitely advocating it as a best opion. Rather, it’s the latest development that has captured the attention of the surgeons at my center who see a significant number of patients with mesothelioma.

-Dr. West

October 28, 2014 at 9:58 pm  #1266772    

shhs

Are you able to comment on the following

“Probably one of the largest changes in the last decade has been the development of drugs addressing specific mutations. From the notion of lung cancer as a disease which takes decades to develop and involves multiple carcinogens, has come a realization that some cancers appear to have a primary mutation. For these cancers, that mutation plays a substantial role and a drug addressing it can have significant impact. For example, many non-smokers may be EGFR (epidermal growth factor receptor) and anti EGFR drugs like Tarceva can have a beneficial impact.”

Thanks

Mike

October 29, 2014 at 4:14 am  #1266774    
JimC Forum Moderator
JimC Forum Moderator

Hi Mike,

Targeted therapies such as those described in your quote have been the focus of much research for several years. As a result, it has become standard practice to test the cancer cells for certain mutations for which targeted drugs have been developed. These mutations occur most often in non-smokers, but they do occur less frequently in smokers, so more oncologists are beginning to test all of their patients.

If you search this site for “targeted therapies” or “EGFR” you will find a wealth of information. You may want to begin with Dr. Pennell’s very thorough overview here.

JimC
Forum moderator


Jul 2008 Wife Liz (51/never smoker) Dx Stage IV NSCLC EGFR exon 19
4 cycles Carbo/alimta, 65% shrinkage
Tarceva maintenance
Mar 2010 progression, added Alimta, stable
Sep 2010 multiple brain mets, WBR
Oct 2010 large pericardial effusion, tamponade
Jan 2011 progression, start abraxane
Jun 2011-New liver, brain mets, add Tarceva
Oct 2011-Dx Leptomeningeal carcinomatosis; pulsed Tarceva
At rest Nov 4 2011
Since then: http://cancergrace.org/blog/jim-and-lisa

October 29, 2014 at 7:26 am  #1266779    
Dr West
Dr West

I think the bigger point is that while we’re extremely aware of the potential importance of mutations in many cancers, though this hasn’t been relevant yet in malignant pleural mesothelioma. This isn’t to say that such mutations/targets couldn’t be helpful for mesothelioma, but they haven’t been shown to be useful yet in that setting.

-Dr. West

October 29, 2014 at 12:17 pm  #1266792    

shhs

I would appreciate comments on

1. Did anything new come out of the South African conference last week?. A Boston based? drug company was presenting information about a new drug they had been trialling

2. I have followed up on SMART therapy – the procedure involves radiation before lung removal – they doubled there 3 year survival rate ( figures of 70 were being quoted). I have asked the question why radiation before the lung removal not after as in the trimodal approach.

3. Are the any other experimental procedures/therapies currently being developed?

Thanks

Mike

October 29, 2014 at 2:18 pm  #1266800    
Dr West
Dr West

Sorry, we don’t keep up with the reports coming out of every meeting around the world. I don’t think this conference in South Africa is very likely to have changed global standards. The important trials are presented at just 1 or 2 main meetings, primarily ASCO (American) and ESMO (European).

I can’t answer the question of the order of SMART protocol. That’s what they did. Bear in mind that the “doubling of three year survival” is not a randomized trial of patients getting one approach or another, but a comparison of results of an earlier cohort of patients compared with a later cohort of patients in a single institution. This is not the same as a definitive test of the utility of one approach compared head to head with another.

There are always new things being worked on, but we can’t address every new agent or trial being looked our around the world.

-Dr. West

November 1, 2014 at 12:44 pm  #1266874    

shhs

Your views on Amatuximab –

Amatuximab is a monoclonal antibody, a type of protein that has been designed to recognise and
attach to a specific structure (called an antigen) that is found on certain cells in the body. Amatuximab
has been designed to attach to mesothelin, a protein that is found in high amounts on the surface of
mesothelioma cells. By attaching to mesothelin, amatuximab is expected to activate certain cells in the
immune system (the body’s natural defences), so that they kill the cancerous cells. This is expected to
slow down the development of malignant mesothelioma.

Thanks Mike

November 1, 2014 at 8:40 pm  #1266877    
Dr West
Dr West

I haven’t seen any clinical research results with amatuximab, so I have no opinion of it. It’s a theoretically appealing focus of research, but I don’t know that I would recommend a patient get on a plane to pursue it.

-Dr. West

November 3, 2014 at 7:01 pm  #1266915    

shhs

Your views on Curcumin

Department of Pathology, University of Vermont College of Medicine, 89 Beaumont Avenue, HSRF 216, Burlington, VT 05405-0068. arti.shukla@uvm.edu.
Abstract
Inflammation is a key mediator in the development of malignant mesothelioma, which has a dismal prognosis and poor therapeutic strategies. Curcumin, a naturally occurring polyphenol in turmeric, has been shown to possess anticarcinogenic properties through its anti-inflammatory effects. Inflammasomes, a component of inflammation, control the activation of caspase-1 leading to pyroptosis and processing of proinflammatory cytokines, interleukin (IL)-1β and IL-18. In the present study, we investigate the role of curcumin in pyroptotic cell death of malignant mesotheliomacells. Using in vitro models with mouse and human malignant mesothelioma cells, curcumin is shown to induce pyroptosis through activation of caspase-1 and increased release of high-mobility group box 1 (HMGB1) without processing of IL-1β and IL-18. Absence of IL-1β processing in response to curcumin-mediated caspase-1 activation is attributed to blockade of pro-IL-1β priming through inhibition of the NF-κB pathway. Furthermore, curcumin’s cytotoxicity in malignant mesothelioma cells is demonstrated to be dependent on pyroptosis as inhibition of caspase-1 resulted in protection against curcumin-induced cell death. We also demonstrate that curcumin-mediated caspase-1 activation is oxidant dependent by using N-acetyl-L-cysteine (NAC) to inhibit pyroptosis. PCR array analysis using the human inflammasome template revealed that curcuminsignificantly downregulated levels of inflammasome-related gene expression involved in inflammation, e.g., NF-κB, toll-like receptors (TLR), and IL-1β. Our data indicate that curcumin has a double effect on malignant mesothelioma cells through induction of pyroptosis while subsequently protecting against inflammation.

November 3, 2014 at 10:14 pm  #1266919    
Dr West
Dr West

This is not clinical research. In my opinion it is of no clinical relevance. I think it is a mistake to chase down every publication on the planet about mesothelioma to try to cobble together an untested plan based on no clinical evidence.

-Dr. West

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